Breast cancer is the most common form of malignancy in women, representing 32% of all new cancer cases and causing 18% of the cancer related deaths among women in the USA. Although the majority of patients with metastatic breast cancer will experience an initial response, survival is only modestly improved with contemporary chemotherapy programs. Consequently, the development of new anti-breast cancer drugs has become a high priority (Abrams, J. S., et al. M. Cancer 1994, 84, 1164).
Human epidermal growth factor (EGF) is a 53 amino acid, single-chain polypeptide (Mr 6216 daltons), which exerts biologic effects by binding to a specific cell membrane epidermal growth factor receptor (EGFR/ErbB-1). Many types of cancer cells display enhanced EGFR expression on their cell surface membranes (Khazaie, K., et al. R. B. Cancer & Metasis Reviews 1993, 12, 255). Enhanced expression of the EGFR on cancer cells has been associated with excessive proliferation and metastasis (Mendelsohn, J. and Baselga, J. Biologic Therapy of Cancer: Principles & Practice 1995, 607). Examples include breast cancer, prostate cancer, lung cancer, head and neck cancer, bladder cancer, melanoma, and brain tumors (Khazaie, K., et al. R. B. Cancer & Metasis Reviews 1993, 12, 255).
In breast cancer, expression of the EGFR is a significant and independent indicator for recurrence and poor relapse-free survival (Toi, M., et al. European J. Cancer 1991, 27, 977; Chrysogelos, S. A. and Dickson, R. B. Breast Cancer Res. Treat. 1994, 29, 29; Fox, S. B., et al. Breast Cancer Res. Treat. 1994, 29, 41). Additionally, it has been shown that the EGFR has an essential function for the survival of human breast cancer cells (Uckun, F. M., et al. Clin. Can. Res. 1998, 4, 901; Moyer, J. D., et al. Cancer Res. 1997, 57(21), 4838). Therefore, the development of PTK inhibitors which abrogate the enzymatic function of the EGFR tyrosine kinase has become a focal point in drug discovery research programs aimed at designing more effective treatment strategies for metastatic breast cancer (George-Nascimento, et al. Biochemistry 1988, 27, 797; Khazaie, K., et al. R. B. Cancer & Metasis Reviews 1993, 12, 255; Fry, D. W. and Bridges, A. J. Curr. Opin. BiotechnoL 1995, 6, 662; Wakeling, A. E., et al. Breast Cancer Research & Treatment 1996, 38, 67).
The primary metabolite of the anti-inflammatory leflunomide N-(4-trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, has been identified as an inhibitor of the EGFR kinase (Parnham, M. J. Exp. Opin Invest. Drugs 1995, 4, 777; Xu, X., et al. Biochem. Pharmacol. 1996, 52, 527; Xu, X., et al. J. Biol. Chem. 1995, 270, 12398; Bertolini, G., et al. J. Med. Chem. 1997, 40, 2011; Mattar, T., et al. A. F. E. B. S. Lett. 1993, 334, 161). Despite the identification of this inhibitor of the EGFR kinase, however, there is a continuing need for novel anti-cancer drugs. In particular, there is a need for anti-cancer drugs which are more potent or more selective than existing drugs. There is also a need for anti-cancer drugs that operate by novel mechanisms, and thus, may be useful against cancers that do not respond to, or have developed resistance to, existing therapies.